CN104447867B - A kind of thieno piperidine derivative, preparation method and applications - Google Patents
A kind of thieno piperidine derivative, preparation method and applications Download PDFInfo
- Publication number
- CN104447867B CN104447867B CN201310428052.4A CN201310428052A CN104447867B CN 104447867 B CN104447867 B CN 104447867B CN 201310428052 A CN201310428052 A CN 201310428052A CN 104447867 B CN104447867 B CN 104447867B
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- China
- Prior art keywords
- acid
- thieno
- pharmaceutically acceptable
- piperidine derivative
- addition salts
- Prior art date
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- MSDZLUHQKBFCHC-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-b]pyridine Chemical class C1CCNC2=C1SC=C2 MSDZLUHQKBFCHC-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 12
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- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- -1 piperidines phosphate derivative Chemical class 0.000 claims description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The present invention relates to a kind of thieno piperidine derivative, preparation method and applications, thieno piperidine derivative of the present invention has following formula（I）Structure, present invention additionally comprises such thieno piperidine derivative as the application for treating and preventing cardiovascular and cerebrovascular diseases medicament.
Description
Technical field
The present invention relates to organic chemistry and medicinal chemistry art.Specifically, the present invention relates to a kind of thieno piperidines to spread out
Biology；The invention further relates to a kind of pharmaceutically acceptable acid addition salts of thieno piperidine derivative, their preparation method, and it
Prepare treat and prevent cardiovascular and cerebrovascular diseases medicament in application.
Background technology
Clopidogrel（Clopidogrel）It is a kind of thiophene pyridines medicine, can efficiently suppresses biologically active pdgf, is mesh
Before be widely used in acute coronary syndrome and the antiplatelet drug of undergoing percutaneous coronary PCI patient.Its structural formula
It is as follows：
Clopidogrel is a kind of inactive pro-drug, it is necessary to by liver cytochrome P 450 (CYP450) enzymatic conversion
Active metabolite is formed, its metabolic process is as follows：
The metabolin and platelet membrane surface adenosine diphosphate (ADP) (adenosine diphosphate, ADP) acceptor P2Y12
With reference to performance blocks the glycoprotein GPIIbPIIIa that ADP is combined with platelet receptor and secondary ADP is mediated complex activating
Effect, so as to suppress platelet aggregation（Arterio-sclerThromb Vase Biol, 1999,19 (8):2002-2011）.
Chlorine pyrroles thunder can substantially reduce the incidence that subacute stent thrombosis is formed in support, reduce the dead, painstaking effort such as stalk of making up one's mind again and run affairs
The generation of part.But research is found recently, about 11%~44%（AmHeart J, 2009,157 (2):375-382.）Patient couple
Chlorine pyrroles's thunder show as low reaction even it is reactionless, this phenomenon be also referred to as " clopidogrel Resistant ".
Therefore, clinic needs to develop rapid-action, curative effect height, can avoid the platelet aggregation-against new drug of clopidogrel Resistant.
The compound favourable to preparation is made is found simultaneously, to improve bioavilability, is reduced side effect, is advantageous to dissolve, absorbs, clothes
With.
The content of the invention：
It is an object of the invention to provide a kind of new clopidogrel metabolin 2- oxygen clopidogrel prodrug thieno piperidines
Derivative, oral administration biaavailability high medicament for resisting platelet aggregation rapid-action so as to develop.
Specifically, be to provide a kind of optical activity thieno piperidine derivative or its medicine can for a purpose of the invention
The salt of receiving, solvate, polymorphs body, enantiomer or racemic mixture.
It is another object of the present invention to provide can be connect with the optical activity thieno piperidine derivative or its medicine
The preparation method of the salt received, solvate, polymorphs body, enantiomer or racemic mixture or pharmaceutical composition.
A further object of the present invention is to provide can be connect with the optical activity thieno piperidine derivative or its medicine
The salt received, solvate, polymorphs body, enantiomer or racemic mixture or the drug regimen that pharmaceutical composition is active component
Thing.
It is yet a further object of the present invention to provide can be connect with the optical activity thieno piperidine derivative or its medicine
The purposes of the salt received, solvate, polymorphs body, enantiomer or racemic mixture or pharmaceutical composition in terms of pharmacy.
Another object of the present invention is to provide can with the optical activity thieno piperidine derivative or its medicine
The salt of receiving, solvate, polymorphs body, enantiomer or racemic mixture or pharmaceutical composition use the medicine group
Compound is used for the method for treating relevant disease.
To achieve these goals, the technical scheme that the present invention takes is as follows：
The present invention, which provides one kind, has formula（I）The optical activity thieno piperidine derivative of structure or its is pharmaceutically acceptable
Salt, solvate, polymorphs body, enantiomer or racemic mixture or pharmaceutical composition：
Wherein, X is P or S, m are 0 or 1, n are 0 or 1, R are that hydrogen, C1-C4 be direct-connected or side chain is optionally substituted by halogen or unsubstituted
Alkyl, phenyl or substituted-phenyl.
Preferably, wherein, X P, m 0, n 0, R are hydrogen, CH3-, CH3CH2-, propyl group, CCL3CH2-, phenyl.Or its
In, X P, m 1, n 1, R are hydrogen, CH3-, CH3CH2-, propyl group, CCL3CH2-, butyl, phenyl.Or wherein, X S, m are
0, n 0, R are hydrogen, CH3-, CH3CH2-, propyl group, CCL3CH2-, butyl, phenyl.
Thieno piperidine derivative of the present invention, it is characterised in that described is following compound：
Present invention additionally comprises the pharmaceutically acceptable acid addition salts of the thieno piperidine derivative, wherein, the salt can be thiophene
Fen and piperidine derivative and sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid,
The salt that methanesulfonic acid, p-methyl benzenesulfonic acid, oxalic acid or butanedioic acid are formed.
The present invention also provides a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition contains thiophene of the present invention
Fen and piperidine derivative or its pharmaceutically acceptable acid addition salts.Described pharmaceutical composition can also contain pharmaceutically acceptable as needed
Carrier.The pharmaceutically acceptable inert carrier can be solid-state or liquid.Pulvis, tablet, dispersible pulvis, capsule can be prepared
The solid or semisolid pharmaceutical formulation of agent, suppository and glue cream form, in the case usually using solid-state carrier.It is workable
Solid carrier is preferably one kind or more in diluent, flavor enhancement, solubilizer, lubricant, suspending agent, adhesive, swelling agent etc.
Kind material, or can be encapsulating substance.In powderous preparations, the micronised active composition containing 5%-70% in the carrier.Suitable
The instantiation of solid carrier includes magnesium carbonate, magnesium stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, Huang
Thermophilic glue, methylcellulose, sodium carboxymethylcellulose, low boiling wax, cocoa butter etc., be easy to due to them administration, tablet, pulvis,
Capsule represents the oral solid formulation of most favorable for absorption.
Liquid preparation includes solution, suspension and emulsion.Such as the injectable formulation of parenteral administration can be water or water
With propylene glycol solution form, the physiological condition that its isotonic degree, pH etc. is suitable to live body is adjusted.Liquid preparation may also be fabricated which polyethylene glycol
Form in the aqueous solution.Can by being dissolved in water active component is molten, add appropriate colouring agent, flavor enhancement, stabilizer and
Thickener, to prepare oral aqueous solution.The active component of micronized can be dispersed in for example natural or synthetic glue of stickum, methyl
Prepared in cellulose, acid methyl cellulose sodium and other known suspending agent and be used in oral water slurry.
Homogeneous for ease of administration and dosage, it is particularly advantageous that said medicine preparation is configured into dosage unit form.
The dosage unit form of preparation refers to the physical separation unit for being adapted as single dose, and each unit, which contains, produces desired control
The active component of the scheduled volume calculated of therapeutic effect.This dosage unit form can be packaged form, such as tablet, capsule or dress
Pulvis in tubule or bottle, or ointment, gel or creme in pipe or bottle.
Although the amount of contained active component can change in dosage unit form, the general active component selected by
Effect, adjust in the range of 1-1000mg.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Typically, treatment is started
Amount is then gradually increased dosage, until reaching optimum therapeuticing effect less than the optimal dose of active component.Rise for convenience
See, total daily dose can be divided into several parts, fraction time administration.
Thieno piperidine derivative of the present invention or its pharmaceutically acceptable acid addition salts are preparing treatment and prevention heart failure
Exhaust, the application in the cardiovascular and cerebrovascular diseases medicament such as apoplexy, unstable angina.Particularly in anti-platelet aggregation medicinal is prepared
Application.
On the other hand, the present invention also provides thieno piperidine derivative of the present invention or its pharmaceutically acceptable salt, solvation
Thing, polymorphs body, enantiomer or racemic mixture, the preparation method include following reactions steps：
Wherein substituent is as previously described.
According to the embodiment of the present invention, compound TSC-9 of the invention can be prepared by following manner：
Wherein, R is chlorine or hydroxyl
The beneficial effects of the present invention are：The invention provides a kind of new change with obvious suppression platelet aggregation
Compound, the compound are clopidogrel metabolite 2- oxygen clopidogrel prodrugs, need not move through CYP2C19 enzymes in vivo i.e.
Metabolizable is 2- oxygen clopidogrels, has rapid-action, curative effect height, while the invention is expected to solve due to Different Individual P450
（Cytoch rome P450, CYP）" clopidogrel Resistant " problem caused by the difference of enzyme system expression.
Embodiment：
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
By 2- oxygen clopidogrel intermediates II（200mg, 0.6mmol）5mL anhydrous tetrahydro furans are dissolved in, are cooled to subzero 20
DEG C, add N-Lithiodiisopropylamide（2.0M,0.5mL,1mmol）Stirring 20 minutes, by compound IIIa（104mg,0.72 mmol）Add
Enter into reaction solution, natural temperature reaction 12 hours, reacted with 4% hydrochloric acid, add 50mL ethyl acetate, use carbonic acid respectively
Hydrogen sodium and saturated common salt washing organic layer, anhydrous sodium sulfate drying, filtering and concentrating.Through silica gel column chromatography（PE:EA=4:1）Purifying,
Obtain compound TSC-1（245mg, yield 92%）.
1H NMR(400MHz,CDCl3):δ7.67-7.65(m,1H),7.42-7.40(m,1H),7.31-7.26(m,2H),
6.25(d,1H),4.91(s,1H),3.87(s,3H),3.72(s,3H),3.64-3.60(m,1H),3.51-3.48(m,1H),
2.89-2.87(m,2H),2.75-2.73(m,2H),MS:m/z446[M+1]+。
Embodiment 2
By 2- oxygen clopidogrel intermediates II（500mg, 1.5mmol）10mL anhydrous tetrahydro furans are dissolved in, are cooled to subzero
20 DEG C, add N-Lithiodiisopropylamide（2.0M,1.25mL,2.5mmol）Stirring 30 minutes, by compound IIIb（311mg,
1.8mmoL）It is added in reaction solution, natural temperature reaction 12 hours, is reacted with 4% hydrochloric acid, adds 100mL ethyl acetate,
Respectively organic layer, anhydrous sodium sulfate drying, filtering and concentrating are washed with sodium acid carbonate and saturated common salt.Through silica gel column chromatography（PE:EA
=4:1）Purifying, obtains compound TSC-2（660mg, yield 93%）.
1H NMR(400MHz,CDCl3):δ7.69-7.66(m,1H),7.43-7.41(m,1H),7.33-7.28(m,2H),
6.27(d,1H),4.91(s,1H),4.27-4.18(m,4H),3.73(s,3H),3.65-3.61(m,1H),3.52-3.49(m,
1H),2.90-2.87(m,2H),2.76-2.74(m,2H),1.39-1.36(dt,6H).MS:m/z474[M+1]+。
Embodiment 3
By 2- oxygen clopidogrel intermediates II（100mg, 0.3mmol）5mL anhydrous tetrahydro furans are dissolved in, are cooled to subzero 20
DEG C, add N-Lithiodiisopropylamide（2.0M,0.25mL,0.5mmol）Stirring 20 minutes, by compound IIId（97mg,0.36mmoL）
It is added in reaction solution, natural temperature reaction 12 hours, is reacted with 4% hydrochloric acid, adds 50mL ethyl acetate, use carbon respectively
Sour hydrogen sodium and saturated common salt wash organic layer, anhydrous sodium sulfate drying, filtering and concentrating.Through silica gel column chromatography（PE:EA=2:1）It is pure
Change, obtain compound TSC-4（162mg, yield 95%）.
1H NMR(400MHz,CDCl3):δ7.71-7.68(m,1H),7.47-7.42(m,5H),7.35-7.24(m,
10H),6.28(d,1H),4.92(s,1H),3.64-3.60(m,1H),3.51-3.48(m,1H),2.89-2.87(m,2H),
2.75-2.73(m,2H),MS:m/z570[M+1]+。
Embodiment 4
By TSC-2（500mg,1.04mmol）It is dissolved in 10mL dry methylene chlorides, adds TMSBr（1.7mL,
13mmol）, 12h is reacted at room temperature, stops reaction, decompressing and extracting solvent, adds 10mL methanol stirring 1h.Reaction solution is directly dense
Contracting, through silica gel column chromatography（N-butanol：Formic acid：Water=5：5：1）Purifying, obtains compound TSC-6（390mg, yield 90%）.
1H NMR(400MHz,DMSO):δ7.60(d,1H),7.53(d,1H),7.41-7.40(m,2H),6.24(s,
1H),4.91(s,1H),3.67(s,3H),3.56(s,2H),2.85(brs,2H),2.66(brs,2H),MS:m/z418[M+1
]+。
Embodiment 5
By 2- oxygen clopidogrel intermediates II（500mg, 1.5mmol）5mL anhydrous tetrahydro furans are dissolved in, are cooled to subzero 20
DEG C, add N-Lithiodiisopropylamide（2.0M,1.25mL,2.5mmol）Stirring 20 minutes, by compound IIIe（466mg,1.8mmoL）
It is added in reaction solution, natural temperature reaction 12 hours, is reacted with 4% hydrochloric acid, adds 100mL ethyl acetate, use carbon respectively
Sour hydrogen sodium and saturated common salt wash organic layer, anhydrous sodium sulfate drying, filtering and concentrating.Through silica gel column chromatography（PE:EA=2:1）It is pure
Change, obtain compound TSC-7（269mg, yield 32%）.
1H NMR(400MHz,CDCl3):δ7.69-7.65(m,1H),7.42-7.40(m,1H),7.31-7.24(m,2H),
6.17(s,1H),5.46(s,1H),5.43(s,1H),4.91(s,1H),3.73(s,3H),3.64-3.60(m,1H),3.50-
3.47(m,1H),2.91-2.88(m,2H),2.75-2.72(m,2H),1.50(s,18H).MS:m/z560[M+1]+。
Embodiment 6
TSC-6 (500mg, 0.89mmoL) is dissolved in 10mL dichloromethane, adds trifluoroacetic acid（2mL）, it is stirred at room temperature
1h, it is concentrated under reduced pressure, through silica gel column chromatography（N-butanol：Formic acid：Water=5：5：1）Purifying, obtains compound TSC-8（140mg, yield
35%）.
1H NMR(400MHz,DMSO):δ7.62-7.60(m,1H),7.54-7.41(m,3H),6.18(s,1H),5.84
(s,1H),5.37-5.32(d,2H),4.26-3.98(m,2H),3.79(s,3H),3.74-3.66(m,2H),3.15-3.00
(m,2H),MS:m/z448[M+1]+。
Embodiment 7
By 2- oxygen clopidogrel intermediates II（500mg, 1.5mmol）5mL anhydrous tetrahydro furans are dissolved in, are cooled to subzero 20
DEG C, add N-Lithiodiisopropylamide（2.0M,1.25mL,2.5mmol）Stirring 20 minutes, compound IV is added in reaction solution, from
Right temperature reaction 12 hours, is reacted with 4% hydrochloric acid, 100mL ethyl acetate is added, respectively with sodium acid carbonate and saturated common salt
Wash organic layer, anhydrous sodium sulfate drying, filtering and concentrating.Through silica gel column chromatography（PE:EA=2:1）Purifying, obtains compound TSC-
9（269mg, yield 32%）.
1H NMR(400MHz,CDCl3):δ7.69-7.65(m,1H),7.42-7.40(m,1H),7.31-7.24(m,
2H),6.17(s,1H),5.46(s,1H),5.43(s,1H),4.91(s,1H),3.73(s,3H),3.64-3.60(m,1H),
3.50-3.47(m,1H),2.91-2.88(m,2H),2.75-2.72(m,2H),1.50(s,18H).MS:m/z560[M+1]+。
The compounds of this invention drug efficacy study of embodiment 8
Experimental method
A small amount of ADP are added in platelet suspension（Concentration is in 0.9 μm of below ol/L）, platelet aggregation can be caused rapidly,
But depolymerization again quickly;If adding the ADP (1.0 μm ol/L or so) of median dose, the first aggregation phase terminate with after depolymerization
Soon, occur second irreversible aggregation phase again.The maximum aggregation rate of irreversible aggrengation phase can be used for evaluating tested
Influence of the product to coagulation function.This experiment gives birth to the semi-automatic platelet aggregation instrument of company's NJ4 types, observation Tian Shi power group using Puli
Inhibitory action by test product to platelet aggregation is provided.
Experiment material：
Animal：Wistar rats male, 230-250g, purchased from dimension tonneau China.
Reagent：ADP, Sigma company.
By test product：7 are provided by test product by Tian Shi power group.
Dosage：It is suspended by test product with 0.25%CMC, the administration of 3mg/kg body weight, administered volume 2ml.
Experimental procedure：
2 hours after rat administration, yellow Jackets anesthesia, abdominal aortic blood, with sodium citrate 1：9 anti-freezings, centrifuging and taking
Platelet rich plasma and platelet poor plasma, both mixed proportions are poor：Rich=3：1.
Experimental result：
The compounds of this invention of table 1 influences on the maximum aggregation rate of ADP induced platelet aggregations
*P<0.001 compared with normal group.
In the experiment of ADP induced platelet aggregations, rat platelet aggregation effect is respectively significantly inhibited by test product, and can
Assembled with the phase of reversing platelet second, cause depolymerization.
Claims (7)
1. one kind has the thieno piperidine derivative or its pharmaceutically acceptable acid addition salts of formula (I) structure：
Characterized in that,
When X is S, and m 0, n are 0, R is hydrogen, CH3-, CH3CH2-, propyl group, butyl, phenyl.
2. thieno piperidine derivative described in claim 1 or its pharmaceutically acceptable acid addition salts, it is characterised in that the compound
For：
TSC-9
3. thieno piperidine derivative described in claim 1 or its pharmaceutically acceptable acid addition salts, it is characterised in that the salt is thiophene
And piperidines phosphate derivative and sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, first
The salt that acid, methanesulfonic acid, p-methyl benzenesulfonic acid, oxalic acid or butanedioic acid are formed.
4. the thieno piperidine derivative or its pharmaceutically acceptable acid addition salts described in claim 1 are preparing treatment and prevention heart failure
Exhaust, the application in the cardiovascular and cerebrovascular diseases medicament of apoplexy, unstable angina.
5. the thieno piperidine derivative or its pharmaceutically acceptable acid addition salts described in claim 1 are preparing anti-platelet aggregation medicinal
In application.
6. a kind of pharmaceutical composition, it is characterised in that the thieno piperidines that described pharmaceutical composition contains described in claim 1 spreads out
Biology or its pharmaceutically acceptable acid addition salts.
7. the pharmaceutical composition described in claim 6, it is characterised in that described pharmaceutical composition is also containing pharmaceutically acceptable
Carrier.
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| CN201310428052.4A CN104447867B (en) | 2013-09-17 | 2013-09-17 | A kind of thieno piperidine derivative, preparation method and applications |
| CA2920410A CA2920410C (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| KR1020167005860A KR20160058098A (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| AU2014323812A AU2014323812B2 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| US14/912,250 US20160200751A1 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| EP14845625.4A EP3048108B1 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| JP2016541790A JP6622205B2 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivatives and uses thereof |
| PCT/CN2014/086191 WO2015039577A1 (en) | 2013-09-17 | 2014-09-10 | Thienopiperidine derivative and use thereof |
| IL244214A IL244214B (en) | 2013-09-17 | 2016-02-22 | Thienopiperidine derivative and use thereof |
| US17/183,616 US20210179632A1 (en) | 2013-09-17 | 2021-02-24 | Thienopiperidine derivative and use thereof |
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| WO2016034103A1 (en) * | 2014-09-02 | 2016-03-10 | 南京曼杰生物科技有限公司 | Substituted tetrahydrothieno pyridine derivatives and use thereof |
| CN107698620A (en) * | 2015-06-23 | 2018-02-16 | 江苏天士力帝益药业有限公司 | A kind of deuterated thieno piperidine derivative, preparation method and applications |
| CN106831870A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | Aryl oxidized phosphine P2Y12 receptor antagonists of one class cyano-thiophene and application thereof |
| CN106831866A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | One aryl oxidized phosphine P2Y12 receptor antagonists of class alcoxyl thiophene and application thereof |
| CN106831869A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | Aryl oxidized phosphine P2Y12 receptor antagonists of amido thiophene and application thereof |
| CN106749408A (en) * | 2017-02-09 | 2017-05-31 | 广东赛博科技有限公司 | A kind of aryl oxidized phosphine P2Y12 receptor antagonists of nitrothiophene and application thereof |
| CN106831868A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | A kind of aryl oxidized phosphine P2Y12 receptor antagonists of amido thiophene and application thereof |
| CN106831871A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | Aryl oxidized phosphine P2Y12 receptor antagonists of one class nitrothiophene and application thereof |
| CN106831867A (en) * | 2017-02-09 | 2017-06-13 | 广东赛博科技有限公司 | A kind of aryl oxidized phosphine P2Y12 receptor antagonists of cyano-thiophene and application thereof |
| CN112778371B (en) * | 2019-11-05 | 2024-01-30 | 华创合成制药股份有限公司 | Thienopyridine derivative and preparation method and application thereof |
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| CN103068383A (en) * | 2010-08-26 | 2013-04-24 | Ipca实验室有限公司 | Methods for the treatment or prophylaxis of thrombosis or embolism |
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| FR2530247B1 (en) * | 1982-07-13 | 1986-05-16 | Sanofi Sa | NOVEL THIENO (3, 2-C) PYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATION |
| FR2576901B1 (en) * | 1985-01-31 | 1987-03-20 | Sanofi Sa | NOVEL DERIVATIVES OF A- (OXO-2 HEXAHYDRO-2,4,5,6,7,7A THIENO (3,2-C) PYRIDYL-5) ACETIC PHENYL, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
| JP2009538899A (en) * | 2006-05-30 | 2009-11-12 | ファイザー・プロダクツ・インク | Triazolopyridazine derivatives |
| US8748596B2 (en) * | 2009-03-18 | 2014-06-10 | Janssen Pharmaceutica Nv | Process for the preparation of histamine H3 receptor modulators |
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| WO2014043895A1 (en) * | 2012-09-21 | 2014-03-27 | 北京普禄德医药科技有限公司 | 2-hydroxyl tetrahydro thienopyridine derivative with optical activity and preparation method and use thereof |
| CN103665042B (en) * | 2012-09-21 | 2016-03-16 | 北京普禄德医药科技有限公司 | Optically active 2-hydroxy tetrahydro thienopyridine derivative and its production and use |
| CN102993210A (en) * | 2012-12-19 | 2013-03-27 | 苏春华 | New thienopyridine compound |
| CN104418891B (en) * | 2013-08-28 | 2018-04-06 | 江苏威凯尔医药科技有限公司 | The preparation of water-soluble 2 hydroxy tetrahydro thienopyridine derivatives and its medical usage |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002053A (en) * | 2009-09-02 | 2011-04-06 | 陕西合成药业有限公司 | Tetrahydro thienopyridine derivative for treating |
| CN103068383A (en) * | 2010-08-26 | 2013-04-24 | Ipca实验室有限公司 | Methods for the treatment or prophylaxis of thrombosis or embolism |
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| AU2014323812A1 (en) | 2016-02-18 |
| US20210179632A1 (en) | 2021-06-17 |
| IL244214B (en) | 2018-08-30 |
| CA2920410A1 (en) | 2015-03-26 |
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| AU2014323812B2 (en) | 2019-06-20 |
| WO2015039577A1 (en) | 2015-03-26 |
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